EBV Conference 2008 Guangzhou - Baylor College of Medicine

198 (RegID: 1731)
Noemi Nagy
Institution: Karolinska Institute, MTC
e-mail: Noemi.Nagy@ki.se
LACK OF FUNCTIONAL SAP MAY LEAD TO EVASION OF APOPTOSIS, A CLUE TO THE
CLINICAL PICTURE OF XLP
Noémi Nagy, Ludmila Matskova, Loránd L Kis, Ulf Hellman (1), George Klein and Eva Klein
Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institute, 17177 Stockholm,
Sweden
(1) Ludwig Institute for Cancer Research, 75124 Uppsala, Sweden
Posterabstract:
Deletion or mutation of the SAP gene is associated with the X-linked lymphoproliferative disease (XLP),
a primary immunodeficiency characterized by unusually serious, often fatal infectious mononucleosis and
by a 200 times higher risk for lymphoma development than the general population. SAP functions have
been linked to signal transduction pathways that control T and NK cell activation/ function. However, our
results show that SAP is involved in other cellular functions as well.
Upregulation of SAP in the late phases of T cell activation suggests a role in T cell homeostasis. In
experiments using clones of the T-ALL line CCRF-HSB2 differing in SAP expression levels, we obtained
evidence that SAP is instrumental in apoptosis. Clones with higher levels of SAP were more prompt to
activation induced cell death (AICD), manifested by caspase activation, PARP cleavage.
Our previous finding that p53 induces SAP expression motivated us to study the impact of SAP in DNA
damaged cells. We found that when SAP was introduced in lymphoblastoid cell lines (LCL) derived from
XLP patients, DNA damage induced significantly higher number of dead cells compared to the original
LCLs that lack SAP.
In an attempt to identify the mechanism of how SAP regulates apoptosis sensitivity, we have performed
immunoprecipitation experiments and found that SAP binds to the anti-apoptotic protein VCP (valosin
containing protein). It is conceivable that by binding VCP, SAP can prevent it from exerting its
anti-apoptotic function, thus a net result being a more pro-apoptotic phenotype of the cells that express
SAP.
Our results suggest that through its involvement in the apoptotic pathways, SAP contributes to the
maintenance of T cell homeostasis and to the elimination of potentially dangerous DNA damaged cells.
This new, pro-apoptotic, function of SAP would explain why XLP patients exhibit uncontrolled T cell
proliferation in fatal IM and develop lymphomas with high frequency.
EBV Conference 2008 Guangzhou
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